VectorB2B

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Toxicology

Expert GLP & Non-GLP Toxicology for Faster, Safer Drug Development

Tailored studies to de-risk and accelerate your pipeline 

The only in vivo TOX GLP certified facilities in Portugal

VectorB2B design and execute your preclinical GLP/ non-GLP toxicology studies, ensuring the success of your drug/ health product development program while meeting global standards and specifications for quality and compliance

Genotoxity

GENERAL IN VIVO TOXICOLOGY

  • Acute Toxicity
  • Sub-acute (28 days) toxicity
  • Sub-chronic (90 days) toxicity
  • Chronic Toxicity
Safety Pharmacology

Safety Pharmacology

  • Central Nervous System – Irwin Test
  • Cardiovascular System – hERG and Purkinje studies
  • Respiratory System – whole body plethysmography

In Vitro Studies

  • Skin sensitization
    (OECD TG 442C,D,E)
  • Skin absorption
    (OECD TG 428)
  • Skin irritation
    (OECD TG 439)
  • Eye irritation
    (OECD TG 492)
  • Skin corrosion
    (OECD TG 431)
  • Phototoxicity
    (OECD TG 432, 498)

Genotoxicity

  • Bacterial Reverse mutation test
    (OECD TG 471, ICH S2 (R1)
  • In vitro MicronucleousTest
    (OECD TG 487, ICH S2 (R1)
  • Mammalian chromosome aberration in vitro
    (OECD TG 473)
Purpose
  • To identify substances that can cause genetic alterations in somatic and/or germ cells;
  • Genetic alterations may result in effects manifested after very long periods of time;
  • Genetic alterations in somatic cells may cause cancer or other genetic diseases;
  • Accumulation of DNA damage can also be related to neurodegenerative diseases;
  • In germ cells, DNA damage is associated with spontaneous abortions, infertility or heritable damage;
  • To adequately cover all genetic endpoints, various tests may be required.
In vitro genetic toxicology tests
  • Bacterial reverse mutation test (Ames test) – OECD 471;
  • In vitro Micronucleus test – OECD 487, 479;
  • Mammalian chromosome aberration in vitro – OECD 473.
In vivo genetic toxicology tests
  • In vivo mammalian erythrocyte micronucleous test – OECD 474;
  • In vivo mammalian alkaline comet assay – OECD 489.
Purpose
  • Studies are performed to determine whether a drug causes on- or off-target acute effects on critical organ systems
  • Dose responses identified in these studies serve to establish a safety margin for the first in human (FIH) dose regimen

Cardiovascular System

  • In vivo, in vitro, and/or ex vivo methods are used to evaluate repolarization and conductance abnormalities;
  • Blood pressure, heart rate, and electrocardiogram;
  • hERG and Purkinje studies (in vitro).
Central Nervous System
  • Motor Activity, behavioral changes, coordination, sensory/motor reflex responses and body temperature should be evaluated;
  • Functional Observational Battery (FOB);
  • Irwin’s Test.
Respiratory System
  • Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation);
  • Evaluation of total respiratory system and the mechanical properties of the lung;
  • Whole-body plethysmography.
Pharmacokinetics (PK)
  • Related to the movement of drug into, through, and out of the body – the time course of its absorption, distribution, metabolism and excretion (ADME);
  • PK is dependent of individual-related factors as well as on the drug’s chemical properties, such as renal function, genetic background, sex, age, etc.
Pharmacokinetics (PD)
  • The study of the biochemical, physiologic, and molecular effects of drugs on the body;
  • Usually it involves receptor binding (as well as receptor sensitivity), post receptor effects, and chemical interactions;
  • PD may be altered by disorders or diseases, age, or the presence of other drugs;
  • Some of the disorders may include malnutrition, genetic mutations or insulin-resistant diabetes mellitus.
PK/PD
  • The exposure-response relationship (PK/PD) is crucial to the development and approval of every drug;
  • PK/PD analyses are important for the understanding of how drugs behave in the body and how the body reacts to drugs;
  • Additionally, they help the design of better clinical studies.
Types of Studies
  • Maximum Tolerated;
  • Dose Dose Range Finding.

General Recommendations and Objectives

  • The current view is that adequate information on acute toxicity can be obtained from other sources than specific single-dose toxicity;
  • “Extended” single-dose toxicity studies evaluate hematology, clinical chemistry, necropsy and histopathology.
Readouts
  • Clinical Signs (morbidity and mortality);
  • Detailed clinical examination at least twice on the day of exposure (this includes changes in skin and fur, eyes, breathing rate, somatomotor activity and behavior;
  • Necropsy;
  • Organ Weight;
  • Fixation.
Guidelines
  • EMA/CHMP/SWP/81714/2010;
  • CHMP/SWP/302413/08;
  • OECD 402, 420, 423, 425.
Types of Studies
  • 14 days;
  • 28 days with recovery period – GLP compliant.

General Recommendations and Objectives

  • Repeated dose toxicity studies should be carried out in two mammal species (one non-rodent); Duration of repeated dose toxicity studies depends on the duration of the proposed therapeutic use in humans;
  • The route of administration should be the same as intended for humans.
Readouts
  • Clinical Signs (morbidity and mortality);
  • Food consumption; body weight;
  • Clinical Examination – tumors, distended abdomen, kyphosis, etc;
  • Ophthalmologic examination – cataracts, eye discharge, corneal opacity, etc;
  • Functional Observational Battery (FOB) – tail stiffening, forelimb grip strength, body temperature, etc;
  • Neuronal Observational Battery (NOB) – gait disorders, tremor, menace reflex;
  • Necropsy;
  • Organ Weight;
  • Fixation.
Guidelines
  • CPMP/SWP/1042/99 Rev. 1 Corr;
  • OECD 407, 410.
Types of Studies
  • 6 to 24 months – GLP compliant.

General Recommendations and Objectives

  • The three main routes of administration used are oral, dermal and inhalation;
  • The study will provide information on the possible health hazards likely to arise from repeated exposure over a considerable part of the lifespan of the species used;
  • Identification of a NOAEL or BMD, as well as a prediction of chronic toxicity effects at human exposure levels.
Readouts
  • Clinical Signs (morbidity and mortality);
  • Food consumption; body weight;
  • Clinical Examination – tumors, distended abdomen, kyphosis, etc;
  • Ophthalmologic examination – cataracts, eye discharge, corneal opacity, etc;
  • Functional Observational Battery (FOB) – tail stiffening, forelimb grip strength, body temperature, etc;
  • Neuronal Observational Battery (NOB) – gait disorders, tremor, menace reflex;
  • Necropsy;
  • Organ Weight;
  • Hematology and Clinical Biochemistry;
  • Histopathology.
Guidelines
  • CPMP/SWP/1042/99 Rev. 1 Corr;
  • OECD 452.
Types of Studies
  • 90 days with recovery period – GLP compliant

General Recommendations and Objectives

  • The same recommendations relevant to sub-acute dose toxicology;
  • 90-days studies provides information on the possible health hazards likely to arise from repeated exposure over a prolonged period of time;
  • The study will provide information on the major toxic effects, indicate target organs and the possibility of accumulation of test chemical, and can provide an estimate of NOAEL;
  • This study provides dose response related data that may be used to estimate point of departure for hazard assessment using appropriate modelling methods.
Readouts
  • Clinical Signs (morbidity and mortality);
  • Food consumption; body weight;
  • Clinical Examination – tumors, distended abdomen, kyphosis, etc;
  • Ophthalmologic examination – cataracts, eye discharge, corneal opacity, etc;
  • Functional Observational Battery (FOB) – tail stiffening, forelimb grip strength, body temperature, etc;
  • Neuronal Observational Battery (NOB) – gait disorders, tremor, menace reflex;
  • Necropsy;
  • Organ Weight;
  • Hematology and Clinical Biochemistry;
  • Histopathology.
Guidelines
  • CPMP/SWP/1042/99 Rev. 1 Corr;
  • OECD 408, 411.
  • Cytotoxicity;
  • The same recommendations relevant to sub-acute dose toxicology;
  • Skin sensitization (OECD TG 442C,D,E);
  • Skin absorption (OECD TG 428);
  • Skin irritation (OECD TG 439);
  • Eye irritation (OECD TG 492);
  • Skin corrosion (OECD TG 431);
  • Phototoxicity (OECD TG 432, 498).